Project Summary/Abstract This SPORE renewal application represents the efforts of interdisciplinary teams of investigators from the Neuro-Oncology Program of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) to apply their knowledge and expertise to translational research focused on brain cancer. This SPORE proposal has three overall specific objectives: 1) to identify factors that contribute to the likelihood of surviving brain cancer; 2) to identify noninvasive imaging parameters that can help predict therapeutic response in patients with glioma; and 3) to develop better mechanism-based therapies for the treatment of brain cancer. The heart of the proposal is four new translational research projects, each driven by teams of applied and basic investigators, and each intended to create novel tools and therapeutic modalities useful in the diagnosis and treatment of brain tumors. Project 1 is a new study motivated by previous SPORE-funded successes in identifying molecular features (TERT promoter mutation, 1p/19q deletion, and IDH1 mutation) that divide lower grade glioma into 4 distinct groups, and along with work from others, led to modifications in WHO criteria for glioma classification. Project 1 investigators now hypothesize that an analysis of levels of various circulating myeloid cells, rather than of tumor molecular features, may yield advances in differentiating prognosis for IDH-wildtype glioblastoma after accounting for certain clinical characteristics. They will test this hypothesis using an approach they pioneered that defines and quantitates aberrant immune cell populations from fresh or frozen peripheral blood based on patterns of DNA methylation in the immune cell genomes, a new field of study called immunomethylomics. Project 2 is a new study facilitated in part by previous SPORE- funded studies that used MRSI to noninvasively define changes in steady state levels of metabolites that related to low-grade glioma progression. In Project 2 the investigators hypothesize that the use of hyperpolarized carbon-13 (C13) imaging, developed at UCSF, can provide complementary information about metabolic processes, which in turn can be used to noninvasively differentiate between normal brain, tumor and gliosis in the human glioblastoma setting. Project 3 is a new study that evolved from groundbreaking work from the Costello lab that identified GABP as the transcription factor that uniquely binds the mutant TERT promoter and drives TERT expression, cellular immortalization and tumorigenesis in many types of cancer including glioma. The work proposed in Project 3 will lay the groundwork for the development of mutant TERT promoter-based therapeutics by assessing the uniformity of TERT promoter mutations in human glioma samples, by directly defining the importance of GABP in TERT activation, and by devising ways to increase cell death following TERT silencing. Project 4 is a new project based on the observation that inhibition of the downstream mTOR target 4EBP is critical for effective growth suppression of PI3K-driven glioblastoma, and that clinical failure of PI3K pathway-targeted therapeutics in glioblastoma is the result insufficient sustained 4EBP suppression. Accordingly Project 4 investigators synthesized an entirely new class of molecules that provide sustained 4EBP suppression and growth inhibition in vivo, and in this project will define the optimal glioma target population for the drug, will optimize the efficacy of the lead agent, and propose the first clinical trial of this new class of agents in glioma patients. This SPORE proposal also requests continued support for the extremely important Career Enhancement and Developmental Research Programs, and for three Cores (Administrative, Biospecimen/Pathology, and Biostatistics and Clinical) that will support the efforts of the four projects. By addressing the overall specific objectives described, the research proposed in this Brain Tumor SPORE application has a high likelihood of changing the way we detect, diagnose, and treat brain cancer.